The compound 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide of the formula 
is described in the European Patent Application with the Publication No. 0 199 262 A2 (EP 199262), for example in Example 4. Valuable pharmacological properties are attributed to this compound; thus, it can be used, for example, as an antiepileptic. The compound 1-(2,6-difluorobenyl)-1H-1,2,3-triazole-4-carboxamide is obtained according to EP 199262, starting from 2,6-difluorobenzyl azide via the formation of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid, the procedure being analogous to Example 2.
EP 199262 provides no information at all about possible crystal modifications obtained. If the method according to the Example 4 is used in conjunction with Example 2, the crude 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide product obtained is finally crystallized from ethanol. However, EP 199262 gives no indication that such recrystallization is specifically to be applied, or on particular conditions that might be adopted. It has now surprisingly been found that the different crystal modifications (polymorphism) characterized below can be prepared by choice of specialty selected process conditions, for example through the choice of an appropriate solvent for the recrystallization or the duration of the recrystallization.
1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide can be obtained in the novel crystal modifications A, Axe2x80x2, B and C. These crystal modifications differ with respect to their thermodynamic stability, in their physical parameters, such as the absorption pattern of IR and Raman spectra, in X-ray structure investigations and in their preparation processes.
The invention relates to the novel crystal modifications A and Axe2x80x2 preparation and use in pharmaceutical preparations comprising the crystal modifications.
The modification Axe2x80x2, compared with A, has defects in the crystal lattice. These are detectable, for example, by X-ray analysis, e.g. by smaller line spacings with otherwise predominantly identical lines or bands.
The novel crystal modification A of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide melts at 242xc2x0 C. (239-245xc2x0 C.).
In the FT infrared (FT-IR) spectrum (KBr pelletxe2x80x94transmission method), modification A or Axe2x80x2 differs from modifications B and C predominantly in the shape and in the relative intensity of many bands. Particularly characteristic are the bands at 3412 cmxe2x88x921 and 3092 cmxe2x88x921 [cf. FIG. 1], which are not present in the Fr-IR spectra of the modifications B and C. In the range 4000-600 cmxe2x88x921, inter alia the following bands are obtained for modification A: 3412, 3189, 3092, 1634, 1560, 1473, 1397, 1325, 1300, 1284, 1235, 1125, 1053, 1036, 1014, 885, 840, 799, 781, 723, 688 and 640 cmxe2x88x921. For example, the apparatus IFS 88 (Bruker) can be used for the recording of each of the FT-IR spectra.
In the FT Raman spectrum (powderxe2x80x94reflection method 180xc2x0), the modification A or Axe2x80x2 differs from modifications B and C predominantly in the shape and in the relative intensity of many bands. Particularly characteristic are the band at 1080 cmxe2x88x921 [cf. FIG. 2], which is not present in the Raman spectra of the modifications B and C. In the range 3400-300 cmxe2x88x921, inter alia the following bands are obtained for the modification A: 3093, 2972, 1628, 1614, 1558, 1465, 1446, 1393, 1279, 1245, 1147, 1080, 1061, 1036, 1014, 840, 724, 691, 667, 550, 499, 437 and 368 cmxe2x88x921. For example, the apparatus RFS 100 (Bruker) can be used for the recording of each of the FT Raman spectra.
The novel modification A has an X-ray powder pattern with characteristic lines with interplanar spacings (d values) of 10.5 xc3x85, 5.14 xc3x85, 4.84 xc3x85, 4.55 xc3x85, 4.34 xc3x85, 4.07 xc3x85, 3.51 xc3x85, 3.48 xc3x85, 3.25 xc3x85, 3.19 xc3x85, 3.15 xc3x85, 3.07 xc3x85, 2.81 xc3x85 [cf. Table 1]. The measurement can be carried out, for example, in transmission geometry on an FR 552 Guinier camera from Enraf-Nonius, Deft (The Netherlands), using copper Kxcex11 radiation (wavelength xcex=1.54060 xc3x85). The patterns recorded on X-ray film were measured using an LS-18 line scanner from Johannsson, Txc3xa4by (Sweden) and evaluated using the Scanpi software (P. E. Werner, University of Stockholm).
Characteristic for the novel modification A is the thermogram in differential scanning calorimetry. It has an endothermic peak in the range from 230xc2x0 C. to 260xc2x0 C. The peak temperature is 239-245xc2x0 C., and the endothermic signal is 209 J/g+/xe2x88x9210 J/g. The measurement was carried out on a Perkin Elmer DSC 7 in a closed pan with a heating rate of 20 K/minute. The typical sample quantity is about 4 mg. As a typical distinguishing feature compared with the modifications B and C, the thermogram of the modification A has no further thermal signal.
Crystals of the modfication Axe2x80x2 have the same crystal structure as modification A. They differ from the modification A in the X-ray powder pattern in that they have slightly smaller line spacings between specific pairs of lines. These are the pairs of lines with the following interplanar spacings: 3.68 xc3x85 and 3.64 xc3x85, 3.51 xc3x85 and 3.48 xc3x85, 3.19 xc3x85 and 3.15 xc3x85.
In the FT-IR spectrum (KBr pelletxe2x80x94transmission method), the modification B differs from the modification A or Axe2x80x2 and C predominantly in the shape and in the relative intensity of many bands. Particularly characteristic is a band at 1678 cmxe2x88x921 [cf. FIG. 1], which is not to be observed in the corresponding spectra of the modifications A and C. In the range 4000-600 cmxe2x88x921, inter alia the following bands are obtained for the modification B: 3404, 3199, 3125, 1678, 1635, 1560, 1475, 1393, 1357, 1322, 1286, 1237, 1051, 1036, 1028, 889, 837, 800, 719, 667 and 645 cmxe2x88x921. For example, the apparatus IFS 85 (Bruker) can be used for recording of each of the FT-IR spectra.
In the FT Raman spectrum (powderxe2x80x94reflection method 180xc2x0), the modification B differs from the modifications A or Axe2x80x2 and C predominantly in the shape and in the relative intensity of many bands. Particularly characteristic are the bands at 3166 cmxe2x88x921 and 1086 cmxe2x88x921 [cf. FIG. 2], which are not present in the Raman spectra of the modifications A and C. In the range 3400-300 cmxe2x88x921, inter alia the following bands are obtained for the modification B: 3166, 3089, 2970, 1678, 1628, 1614, 1559, 1464, 1441, 1391, 1275, 1244, 1147, 1086, 1062, 1036, 1014, 839, 773, 724, 690, 668, 595, 549, 500, 493, 430 and 365 cmxe2x88x921. For example, the apparatus RFS 100 (Bruker) can be used for recording of each of the Fr Raman spectra.
The modification B has an X-ray powder pattern with characteristic lines with interplanar spacings (d values) of 11.0 xc3x85, 8.3 xc3x85, 5.18 xc3x85, 4.88 xc3x85, 4.80 xc3x85, 4.42 xc3x85, 4.33 xc3x85, 4.19 xc3x85, 4.12 xc3x85, 3.81 xc3x85, 3.50 xc3x85, 3.41 xc3x85, 3.36 xc3x85, 3.32 xc3x85, 3.28 xc3x85, 3.24 xc3x85, 3.05 xc3x85, 2.83 xc3x85 [cf. Table 1].
In the thermogram in differential scanning calorimetry, the modification B has, in addition to an endothermic signal in the range from 230xc2x0 C. to 260xc2x0 C. (peak temperature 239-245xc2x0 C.), a weak thermal signal at 205xc2x0 C. (180-220xc2x0 C.) as a typical distinguishing feature compared with the modifications A or Axe2x80x2 and C.
In the FT-IR spectrum (KBr pelletxe2x80x94transmission method), the modification C differs from the modifications A or Axe2x80x2 and B predominantly in the shape and in the relative intensity of many bands. Particularly characteristic is a band at 3137 cmxe2x88x921 [cf. FIG. 11], which is not to be observed in the corresponding spectra of the modifications A and B.
In the range 4000-600 cmxe2x88x921, inter alia the following bands are obtained for the modification C: 3396, 3287, 3137, 1657, 1631, 1602, 1559, 1475, 1392, 1323, 1287, 1237, 1122, 1104, 1047, 1035, 1012, 876, 839, 797, 773, 729 and 653 cmxe2x88x921. For example, the apparatus IFS 85 (Bruker) can be used for recording of each of the FT-IR spectra.
In the FT Raman spectrum (powderxe2x80x94reflection method 180xc2x0), the modification C differs from the modifications A or Axe2x80x2 and B predominantly in the shape and in the relative intensity of many bands. Particularly characteristic are the bands at 3137 cmxe2x88x921 and 1602 cmxe2x88x921 [cf. FIG. 2], which are not present in the Raman spectra of the modifications A and B. In the range 3400-300 cmxe2x88x921, inter alia the following bands are obtained for the modification C: 3137, 3080, 3012, 2971, 1673, 1629, 1602, 1561, 1436, 1271, 1248, 1105, 1065, 1035, 1013, 839, 800, 767, 726, 690, 672, 593, 549, 500, 492, 435 and 370 cmxe2x88x921. For example, the apparatus RFS 100 (Bruker) can be used for recording of each of the FT Raman spectra.
The modification C has an X-ray powder pattern with characteristic lines with interplanar spacings (d values) of 9.0 xc3x85, 4.73 xc3x85, 4.65 xc3x85, 3.75 xc3x85, 3.54 xc3x85, 3.42 xc3x85, 325 xc3x85 [cf. Table 1]. In the thermogram in differential scanning calorimetry, the modification C has, in addition to an endothermic signal in the range of 230xc2x0 C. to 260xc2x0 C. (peak temperature 239-245xc2x0 C.), a very broad, weak, exothermic signal in the region of 180xc2x0 C. compared with the modifications A or Axe2x80x2 and B.
Single Crystal X-ray Analysis
Crystal quality and unit cell of modifications A, B, and C were verified by Weissenberg and precession photographs. The intensities were measured on a four-axis Nonius CAD-4 diffractometer. The structures were solved with the SHELXS-97 and refined with the SHELXL-97 software.
Space group: Pna21xe2x80x94orthorhombic
Cell dimensions:
9011 unique reflections; 2479 thereof significant with I greater than 2"sgr" (I). 557 parameters refined. Position of all H atoms found by difference Fourier maps and refined isotropically. Reliability index R1: 3.65% (wR2 for all 9011 reflections: 11.34%).
Space group: Pxe2x88x921xe2x80x94triclinic
Cell dimensions:
4934 unique reflections; 834 thereof significant with I greater than 2"sgr" (I). 232 parameters refined. Position of all H atoms found by difference Fourier maps and refined isotropically. Reliability index R1: 4.20% (wR2 for all 4934 reflections: 7.93%).
Space group: P21/Cxe2x80x94monoclinic
Cell dimensions:
3073 unique reflections; 1071 thereof significant with I greater than 2"sgr" (I). 187 parameters refined. Position of all H atoms found by difference Fourier maps and refined isotropically. Reliability index R1: 5,02% (wR2 for all 3073 reflections: 14.55%). Modifications A, Axe2x80x2, B and C have valuable pharmacological properties; in particular, they can be used for the treatment of epilepsy.
The modification A or Axe2x80x2 has significant advantages compared with the modification B and compared with the modification C. Thus, for example, comprehensive thermodynamic investigations such as thermomicroscopy, X-ray powder diffractometry, DSC, solubility tests and other experiments, have shown that the modification A or Axe2x80x2 surprisingly has substantially better thermodynamic stability than the modifications B and C. Modification C, which can be obtained only under specific conditions, is the least stable of the three modifications. The crystals of the modification C are converted into modification B at as low as room temperature within a few weeks. The modification C is converted either into the modification A or Axe2x80x2 or into the modification B, depending on experimental conditions.
It is particularly important for a drug that its pharmaceutical formulation ensures high and reproducible stability over a long period. These preconditions are fulfilled by incorporation of the compound 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide of the crystal modification A or Axe2x80x2, owing to its high thermodynamic stability. In particular, this is displayed in a solid pharmaceutical dosage form.
A constant stability also permits reproducible bioavailability of an active ingredient. If an active ingredient is subjected to a conversion process, this may readily also cause the bioavailability to fluctuate, which is undesirable. Accordingly, pharmaceutical active ingredients or polymorphic forms thereof which are of primary interest for pharmaceutical developments are those which exhibit high stability and do not have the above-mentioned disadvantages. The crystal modification A or Axe2x80x2 fulfills these preconditions.
Furthermore, the modification A or Axe2x80x2 has, for example, a slower dissolution rate in water or in gastric fluid (so-called xe2x80x9cslow-release effectxe2x80x9d). This effect can be utilized primarily for long-term therapy where a slow or delayed release is desired.
The invention relates to the modification A of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, characterized by the following absorptions in the infrared spectrum (KBr pelletxe2x80x94transmission method): bands at 3092 cmxe2x88x921 and 3412 cmxe2x88x921.
The invention relates to the modification A of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, characterized by characteristic lines with interplanar spacings (d values) of 10.5 xc3x85, 5.14 xc3x85, 4.84 xc3x85, 4.55 xc3x85, 4.34 xc3x85, 4.07 xc3x85, 3.51 xc3x85, 3.48 xc3x85, 3.25 xc3x85, 3.19 xc3x85, 3.07 xc3x85 and 2.81 xc3x85, determined by means of an X-ray powder pattern.
The invention relates to the modification A of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, characterized by the characteristic lines with interplanar spacings (d values) as shown in Table 1.
The invention relates to the modification A of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, characterized by an endothermic peak in the range from 230xc2x0 C. to 260xc2x0 C., the peak temperature being 239-245xc2x0 C. and the endothermic signal being 209 J/g+/xe2x88x9210 J/g.
Furthermore, the invention relates to the crystal modification Axe2x80x2 which, compared with modification A, has defects in the crystal lattice.
The invention relates to the modification Axe2x80x2 which, compared with modification A, has smaller line spacings between the pairs of lines with interplanar spacings 3.68 xc3x85 and 3.64 xc3x85, 3.51 xc3x85 and 3.48 xc3x85 and 3.19 xc3x85 and 3.15 xc3x85.
The invention relates to the essentially pure form of the modification A or Axe2x80x2 of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide. The term xe2x80x9cessentially pure formxe2x80x9d means purity of  greater than 95%, in particular  greater than 98%, primarily  greater than 99%, based on the modification A or Axe2x80x2.
The invention relates to pharmaceutical preparations comprising the modification A or Axe2x80x2 of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide. The invention relates in particular to corresponding pharmaceutical preparations for the treatment of epilepsy and subindications thereof. The invention relates to the use of the modification A or Axe2x80x2 of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide for the preparation of pharmaceutical preparations, in particular for the treatment of epilepsy and subindications thereof.
The novel modification A or Axe2x80x2 of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide can be used, for example, in the form of pharmaceutical preparations which comprise a therapeutically effective amount of the active ingredient, if desired together with inorganic or organic, solid or liquid, pharmaceutically usable carriers, which are suitable for enteral, for example oral, or parenteral administration. Furthermore, the novel modification A or Axe2x80x2 of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide can be used in the form of preparations which can be administered parenterally or of infusion solutions. The pharmaceutical preparations may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations comprise from about 0.1% to 100%, in particular from about 1% to about 50%, of lyophilisates to about 100% of the active ingredient.
The invention also relates to the use of modification A or Axe2x80x2 of 1-(2,6-difluorobeanzyl)-1H-1,2,3-triazole-4-carboxamide as a drug, preferably in the form of pharmaceutical preparations. The dosage may depend on various factors, such as method of administration, species, age and/or individual condition. The doses to be administered daily are between about 0.25 and about 10 mg/kg in the case of oral administration, and preferably between about 20 mg and about 500 mg for warm-blooded species having a body weight of about 70 kg.